Highly drug resistant forms of tuberculosis termed multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis are on the rise worldwide raising the specter that this disease may once again become virtually incurable. Through two government sponsored screening programs (the MLSCN and TAACF), a large amount of preliminary high throughput screening (HTS) data will soon become available to the research public relating to the discovery of compounds that might target highly drug resistant forms of tuberculosis. Unfortunately, these data are early stage preliminary results, and active compounds from these screens need further translation through the tuberculosis drug discovery pipeline. Oftentimes, however, individual researchers do not readily have access to the funds or tools required to properly prioritize the vast amounts of HTS data into specific scaffolds for further medicinal chemistry and drug development. It is our intention to carry out the appropriate early stage exercises necessary to translate this vast set of preliminary data into manageable information that will help the community and small biotech companies to focus on the best compound classes in their efforts to pursue new drugs against tuberculosis. Specifically, we will cluster the total data set of available HTS information into active sets of compounds that have good medicinal chemistry properties and minimal reactive functions;sets will be selected based on dissimilarity to known antitubercular drugs and known literature citations. With this information we will carry out chemistry through commerce, buying an initial follow up set of compounds in approximately ten of the top clusters for a total of 1,000 compounds. These samples will be screened in a variety of assays used for prioritizing potential new antitubercular drugs. From these results, a subset of 300 compounds will be identified and purchased in 3-5 of the most active clusters in order to flesh out a more thorough structure-activity relationship. Further screens are proposed to add value to the specific compounds chosen. Such an approach is more efficient in terms of time and money, and this program should help readily move the large screening data into focused drug discovery programs in the community. The proposed studies are anticipated to result in ten highly active clusters of compounds showing interesting antitubercular activity in a series of accepted panels of screens for new drug discovery candidates. Furthermore, we expect to identify approximately three classes of compounds showing significant activity throughout the prioritization panel including activity against MDR and XDR tuberculosis strains;these candidates should be a high priority for future drug discovery programs. Broadly, this application addresses the challenge of pursuing the development of new drugs for the treatment of drug resistant forms of tuberculosis, particularly MDR and XDR strains. Specifically, this program will continue the advancement of preliminary active compounds from the TAACF program further along the development pipeline. In terms of an impact, the goal of this application will be to bring data for a select set of compounds that have promise for new drug discovery into the public and commercial domain for further advancement towards new antitubercular agents to treat drug resistant disease. PUBLIC HEALTH RELEVANCE: Highly drug resistant forms of tuberculosis termed multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis are on the rise worldwide raising the specter that this disease may once again become virtually incurable. Through two government sponsored screening programs (the MLSCN and TAACF), a large amount of preliminary high throughput screening (HTS) data will soon become available to the research public relating to the discovery of compounds that might target highly drug resistant forms of tuberculosis. Unfortunately, these data are early stage preliminary results, and active compounds from these screens need further translation through the tuberculosis drug discovery pipeline. Oftentimes, however, individual researchers do not readily have access to the funds or tools required to properly prioritize the vast amounts of HTS data into specific scaffolds for further medicinal chemistry and drug development. It is our intention to carry out the appropriate early stage exercises necessary to translate this vast set of preliminary data into manageable information that will help the community and small biotech companies to focus on the best compound classes in their efforts to pursue new drugs against tuberculosis. Such an approach is more efficient in terms of time and money, and this program should help readily move the large screening data into focused drug discovery programs in the community. The proposed studies are anticipated to result in ten highly active clusters of compounds showing interesting antitubercular activity in a series of accepted panels of screens for new drug discovery candidates. Furthermore, we expect to identify approximately three classes of compounds showing significant activity throughout the prioritization panel including activity against MDR and XDR tuberculosis strains;these candidates should be a high priority for future drug discovery programs.